Lecture 3: Tourette's

Question 1

Tourette’s Disorder

In 1885, Gilles de la Tourette described patients who suffered from a disorder characterized by involuntary movements, echolalia (repeating others speech), coprolalia (repetitive speech patterns), and unusual, uncontrollable sounds

Answer 1

Definition
• Multiple motor tics and one (or more) vocal
tics that have persisted for more than one
year.
• A tic is a sudden, recurrent, rapid, and
stereotyped vocalization or movement that
can either be simple or complex.

• Simple motor tics:
o Eye blinking,
o nose wrinkling,
o shoulder shrugging

• Complex motor tics:  
o	Jumping, 
o	pressing, 
o	stomping, 
o	squatting, 
o	twirling, 
o	hand gestures 

• Simple vocal tics: 
o	Throat clearing, 
o	sniffing, 
o	chirping, 
o	snorting 

• Complex vocal tics:
o Sudden expression of a single word or
phrase (echolalia)

Contrary to popular believe, coprolalia (sudden and inappropriate expression of obscenities, racial or religious slurs) is not a diagnostic criterion for Tourette’s disorder. Coprolalia is only seen in 10-25% of Tourette’s cases.

Question 2

Prevalence

Answer 2

• In the United States: 3-8 per 1,000 children
and 0.05% of adults
• Prevalence varies among countries
o Lower rates reported in African Americans,
sub-Saharan Africans, Japan and Taiwan
• Male to female ratio of 4:1
• Mean age of tic onset is 6.4 years (child
onset)
• Symptoms vary overtime
• Tics often decline during adolescence, but
many individuals continue to struggle with
tics into adulthood
• For example, after 16 years, 17.7% had no
tics, 59.5% had minimal or mild tics, and
22.8% had moderate or severe tics

Question 3

Definition

• Premonitory urges

Answer 3

Definition
• Premonitory urges refer to the
uncomfortable sensation which typically
precede tics and individuals report feeling
of release follow the expression of the tic
o Premonitory urges in childhood and are
associated with increased neural activity in
the insula and pathways extending from
the basal ganglia to the frontal cortex

Question 4

Comorbidity

Answer 4

Comorbidity
• Comorbid conditions to Tourette’s 
  commonly develop in childhood and reduce 
  quality of life:
o	Sleep disturbances
o	Inappropriate sexual behavior
o	Social, academic, neuropsychological, 
        and occupational impairment
o	Self-injurious behavior (occasionally)
o	Greater risk for being bullied by their 
        peers
o	Low self-esteem, anxiety, and 
        depression 
o	86% of Tourette’s cases have a single 
        comorbid psychiatric condition and 58% 
        of individuals with Tourette’s have two or 
        more psychiatric disorders
o	Two most common comorbid conditions:
•	ADHD (35–90%) 
•	OCD (35–50%) 
o	Other comorbid conditions:
•	Explosive rage (25–75%)
•	Depression (13–76%)
•	Learning disabilities (23%)
•	Migraine headaches (25%)
• Comorbidities typically occur between     
  ages 4-10 but eating and substance 
  disorders tend to emerge in adolescents.

Question 5

Genetics Findings

Family and twin findings

Answer 5

Family and twin findings
• Tourette’s is more common in first (10-100x
higher) and second degree relatives
• 3x higher in children if both (rather than
one) parent has Tourette’s
• Heritability estimates range from 53% to
63% for monozygotic
• Heritability estimates range from 8% to 33%
for dizygotic
• There is a genetic component to Tourette’s
but these rates are lower than for ASD,
ADHD, schizophrenia, and bipolar disorder

Question 6

Linkage studies and candidate genes

Answer 6

• No single gene has been identified as
causing Tourette’s disorder
o Suggesting that Tourette’s is a genetically
complex disorder and not the result of a
single genetic mutation.
• Focus of genetic studies include
chromosomes 1, 3, 4, 5, 6, 9, 11, 13, 17, 22
o Based on neurobiological theories of
Tourette’s which implicate the frontal-
striatal pathways, the associated
neurotransmitters (dopamine, serotonin,
and glutamate) and histamine genes.

Question 7

Dopamine

Answer 7

• Dopamine was implicated in Tourette’s due
to evidence that stimulants worsen tics in
~25% of individuals with Tourette’s disorder
• Dopamine related genes (transporter,
receptors) have been investigated
o E.g., D1 & D5
o Results have been inconsistent

Question 8

D2 receptor

Answer 8

• Polymorphism of DRD2 (restriction
fragment length) associated with increased
risk of Tourette’s disorder (particularly in
Caucasians)
o Located on chromosome 11
o Increased density of the D2 receptor in the
frontal region and striatum of individuals
with Tourette’s relative to controls
o Only a small percentage of Tourette’s
cases present with the DRD2 gene variant,
and it is also linked to schizophrenia and
substance use disorder

Question 9

Dopamine transporter gene (DAT1/SLC6A3)

Answer 9

• Located on chromosome 5, encodes the 
  dopamine transporter protein in the 
  presynaptic membrane. Dopamine 
  transporter proteins retrieves dopamine 
  from the synaptic cleft following 
  exocytosis.
• Linked to Tourette’s disorder 
• Increased density in the striatum (37% to 
  50%)

*Candidate gene studies have produced
insignificant findings and overlap with
other disorders. There is no gene[s] which
reliably predict risk of developing
Tourette’s

Question 10

Structural findings

Gray and White Matter

Answer 10

Gray and White Matter
• Lower white matter in the prefrontal cortex
• Greater gray matter in the thalamus,
midbrain hypothalamus
o Lower white matter volume is positively
correlated with tic severity and duration
o Are these morphological differences
associated with the disorder or
medication?

Reading:
• Increased white matter volume in the
parietal regions, smaller occipital volumes
which correlates with severity of symptoms
(older finding)
• Reduced gray matter thickness in the insula
and sensorimotor cortex which was
inversely related to tic severity and
premonitory urges (i.e., reductions in gray
matter volume is associated with increased
symptom severity)

Question 11

Are structural changes induced by medication?

sulci
enlarged ventricals

Answer 11

• To support the theory that white/gray
matter volume reductions maybe due to
medication comes from one study which
compared brain matter volume between
unmedicated children with Tourette’s and
healthy controls. They did not find any
significant structural changes between
children with Tourette’s not treated with
medication and HC’s.
• So maybe medication?

Sulci
• Lower depth and reduced thickness of gray
matter in the sulci

Reading:
• Mixed findings about ventricle enlargement
and is not unique to Tourette’s and is seen
in chronic substance use and
schizophrenia.

Question 12

Basal ganglia

Answer 12

Basal ganglia
• Smaller basal ganglia
• Lack normal symmetry (left larger than right)
• Cerebral strokes that affect the basal
ganglia often result in subsequent tics and
other symptoms of Tourette’s

Reading:
• Structural differences in the basal ganglia
are not unique to Tourette’s and is also
seen in ASD, ADHD, and OCD
• Mixed findings about structural differences
in the corpus callosum (cavum septum
pellucidum) that fuses in early development
was significantly smaller in children with
Tourette’s but other studies failed to
replicate this.
• Structural findings are correlational in
nature! Whilst informative we do not know if
they cause Tourette’s or vice versa.

Question 13

Functional findings (PET)

Answer 13

Functional findings (PET)
*Due to vocal and motor tics being
characteristic of Tourette’s studies have
focused on subcortical regions linked to
movement (basal ganglia) and the pathways
extending from these areas to the frontal
cortex (i.e., the cortico-basal ganglia circuits)

• Increased binding to (D2) in the caudate
nucleus in the affected monozygotic twin
(no differences in the putamen)

Question 14

Analysis of postmortem tissue

Answer 14

Analysis of postmortem tissue
• 140% increase in prefrontal D2 receptor
binding
• Increases in dopamine transporters
• Increases in metabolite concentration of
dopamine and norepinephrine in prefrontal
and striatum regions in individuals with
Tourette’s

Question 15

Basal ganglia

Answer 15

Basal ganglia
• Evidence of functional differences in the
basal ganglia in individuals with Tourette’
o Following an intravenous injection (injected
directly into veins) of amphetamine those
with Tourette’s disorder had significant
increased dopamine release (21%) in the
putamen relative to controls (controversial)

Question 16

Speculations

Answer 16

Speculations
• Based on findings that there are functional
differences in the basal ganglia some
speculate that overactive dopamine
transporter system in the basal ganglia,
underlie Tourette’s disorder
o Evidence: Dopamine agonists (stimulants)
exacerbate Tourette symptoms in some
(but not all) individuals
o Others have suggested that increased
activity in the basal ganglia indicate
defects in brain maturation

Reading:
• Increased presynaptic dopamine activity in
the caudate and/or putamen
• During coprolalia (verbal tics) was
associated with increased activity in the
caudate nucleus, cingulate gyrus, occipital,
and frontal regions
• Increased activity in the striatum (caudate
and putamen) and the prefrontal cortex

Question 17

Suppression of tics

Answer 17

Suppression of tics
• Examining functional differences in brain activity during voluntary tic suppression and tic expression.
• During tic expression (relative to suppression):
o Increased activation in the frontal cortex and right caudate nucleus
o Decreased activation in the globus pallidus
• Frontal regions appear to fail to exert control over motor pathways in individuals with Tourette’s which results in tic expression.

*Tourette’s effects the frontal regions and not just the basal ganglia

Question 18

Glucose metabolism

Answer 18

Glucose metabolism
• Increases, decreased and no change
results
• Conflicting results!

Reading:
• Decreased glucose metabolism in
prefrontal orbitofrontal, hippocampal
regions, and the striatum in medication
naïve individuals
• Increased activity (glucose metabolism) in
the premotor, anterior cingulate cortex,
putamen, caudate, and primary motor
cortex which was linked to tic presence
• Increased glucose metabolism in the
premotor and motor cortex, and decreased
activity in the caudate, thalamus, and
hippocampal regions
• rCBF have been mixed. Some report
increased in rCBF in the frontal regions and
others reductions in the frontal and striatal
regions

Question 19

Current consensus (basal ganglia)

Answer 19

Current consensus (basal ganglia)
• Abnormalities in the basal ganglia
(putamen, caudate, and globus pallidus;
linked to movement) can result in Tourette’s
disorder
• Different parts of the basal ganglia may
affect motor and cognitive symptoms
• The cause of alterations of the basal
ganglia are the result of genetic and
structural differences and possibly
epigenetic factors

Question 20

Current consensus (limbic system)

Answer 20

Current consensus (limbic system)
• Functional findings implicate the frontal
and limbic regions being involved in
Tourette’s
o Conscious suppression of tics is possible
o Tics reduce in frequency during high
attention demanding tasks
§ E.g., musical performance, listening to
music, or mental imagery of musical
performance
§ Shifting attention away from tics
significantly reduces their frequency
• Stress and emotionally charged situations
exacerbate tics, implicating (limbic regions)

Other Reading to Explain Findings:
• Tics can be associated with neurological
disorders and are thought to be the result
of dysfunctional basal ganglia pathways. In
Tourette Syndrome (TS), excess dopamine
in the striatum is thought to excite the
thalamo-cortical circuits, producing tics.
When external stressors activate the
hypothalamic-pituitary-adrenal (HPA) axis,
more dopamine is produced, furthering the
excitation of tic-producing pathways.
Emotional processing structures in the
limbic are also activated during tics,
providing further evidence of a possible
emotional component in motor ticking
behaviours
• Remember stimulants which increase
dopamine increase tics
• Frontal Lobe = attention, impulsivity, motor,
speech, reward-seeking

Question 21

Pharmacological interventions

Answer 21

• Medication effectiveness varies with 
  symptom severity and medication type
• Medications can reduce symptoms by 25% 
  to 70%
• Use of medication is recommended when 
  symptoms cause social-emotional 
  problems, physical discomfort and/or 
  impairment in daily living.
• Two common medications to treat 
  Tourette’s are 
o	Antipsychotic 
o	Adrenergic alpha-2 medications

*Cognitive Behavioural Therapy are highly
effective in managing tics and is
recommended prior to using medication

Question 22

Antipsychotic medication

Answer 22

• Antipsychotic medications are dopamine
antagonists that block postsynaptic
dopamine receptors to reduce dopamine
release and are highly effective in reducing
Tourette’s symptoms (43-70%)
o Haloperidol/haldol
o Thioridazine/mellaril
o Thiothixene/navane
o Pimozide/orap
• Negative side effects include: weight gain,
drowsiness, and sedation

Question 23

Atypical antipsychotic medication

Answer 23

• They have a different mode of action to
antipsychotics.
• They partially block dopamine receptors
and serotonin receptors
o In some cases they serve as dopamine and
serotonin agonists (increase
neurotransmitter; can act as both
antagonists or agonists)
o Risperidone reduces symptoms by 21 to
61%
• Examples: risperidone, paliperidone,
clozapine, olanzapine, ziprasidone,
quetiapine, aripiprazole, asenapine,
iloperidone, and lurasidone.
• Several studies show risperidone,
paliperidone, clozapine are equally
effective at reducing tics but have fewer
side effects than risperidone.

Question 24

Adrenergic Alpha-2 Agonists medications

Answer 24

• Decreases release of norepinephrine as
well as dopamine and glutamate are
effective at reducing Tourette’s
o 50% of symptom reduction with clonidine
but in 90% of individuals experience side
effects including fatigue and sedation
o Guanfacine: Effective at decreasing motor
and vocal tics
• Improved performance in children with
Tourette’s disorder and comorbid ADHD
• Less sedative effects than clonidine but
can increase mania in individuals with
Tourette’s with a family history of mania
• No more effective than a placebo

Question 25

Alternative interventions (preliminary)

Answer 25

• Marijuana:
• THC reduced symptoms without any
serious side effects
• Safe and effective treatment for tics

• Nicotine:
• Nicotine patch application reduces tics
both short and long term
• Nicotine and dopamine receptors in the
striatum work together and may explain
why nicotine patches can improve tics
(targeting one influences the other)

• Botulinum toxin injections (prevents 
  acetylcholine release)
• Have improved symptoms in other 
  disorders characterized by abnormal 
  muscle contractions
• Botulinum toxin injections in the areas of 
  most severe tics, 84% of the subjects 
  experienced a reduction in premonitory 
  sensations (i.e., urges to tic), and majority 
  showed substantial tic reductions within 3.8 
  days
• In vocal cords, improvement in 93% 
  percent of patients and 50% became 
  completely tic free and significant 
  reduction premonitory sensations
• However, these studies have been poor 
  quality

Question 26

Neurosurgery and brain stimulation techniques

Answer 26

• The target sites of ablation (psychosurgery)
varies and includes the frontal lobes, limbic
system, thalamus, and cerebellum.
• Study: Anterior cingulotomy reduced tics
short and long-term in individuals with
comorbid Tourette’s and OCD
• Study: 11 patients with Tourette’s disorder
who underwent surgical treatment (lesion
of the thalamus)
o Vocal and motor tics and premonitory
urges were substantially reduced
o 68% of patients experienced side effects:
Confusion, attention problems, numbness,
and loss of muscle control

Question 27

Deep brain stimulation

Answer 27

• Promising alternative to lesion surgery
• Chronic pulse generators were implanted
in the region of the thalamus
o Follow-up assessments (8 months to 5
years) indicated that major vocal and
motor tics had disappeared.
o Side effects were observed (fatigue and
changes in sexual behaviour)
o DBS is an effective and relatively safe
treatment for severe, intractable Tourette’s
disorder.

Question 28

Repetitive TMS

Answer 28

Repetitive TMS
• Preliminary evidence shows rTMS applied
to the supplemental motor cortex of
participants with Tourette’s disorder has
shown promising therapeutic effects in
reducing symptoms

Question 29

Does strep throat cause Tourette’s disorder?

Answer 29

Does strep throat cause Tourette’s disorder?
• Streptococcal infections can play a critical
role in the development of TD
o Unclear how this occurs
o People speculate Tourette’s disorder is an
autoimmune response to Streptococcal
infections, known as PANDAS
o Not everyone exposed to the streptococcal
develops TD, not everyone who has TD has
had streptococcal
o Individuals with PANDAS which develop
Tourette’s have increased basal ganglia
volumes presumably due to increased
antibodies in the basal ganglia
o Titers were significantly higher in
participants with TD relative to
schizophrenia and healthy controls
o Antineuronal bodies may bind to neurons
in the striatum, produce functional changes
in these cells which lead into TD
• Neuroimaging implicate PANDAS in the
development of Tourette’s disorder
• PANDAS (Pediatric Autoimmune
Neuropsychiatric Disorder Associated with
Streptococcal Infections)

Question 30

Class Discussion:

Answer 30

Class Discussion:
• “In 1949, the Portuguese neurologist
Antonio Egas Moniz received the Nobel
prize in physiology or medicine for his
development of the prefrontal lobotomy”
• At the time lobotomy was incredible, they
thought they had solved schizophrenia.
They’ll fix you. He got a noble prize. They
drove an ice pick into the brain to destroy
the pre-frontal cortex to get rid of voices, a
cure for hallucinations. Today this is
considered barbaric, unethical, makes
individuals into a vegetable, you’ve
changed the person and their behaviour
(disorder) is that good? A philosophical
question. To destroy behaviour that is
socially considered unacceptable
behaviour. Just because something works
means it’s right. There are consequences to
the changes we make. Is It worth it? Do we
really need to change it? Where do we draw
the line? What is our goal?

• He gives people the option to the individual
on whether they want the treatment to
accept the risks. You do not save people.
You give the option if the person wants it.
We do not have answers, just behaviour
modification techniques.
• We still have such an impaired
understanding of the physiology of
disorders we still use brain stimulation or
surgery in high-risk cases like we did in the
past. Where is the line?

• Ted-talks, media, commonly falsely claim
cures for disorders. We know very little.
• Disorders precede human culture. Suicide,
drug addiction etc. is in primates (before
human civilization) indicating that the
genetic component. Culture moderated
disorders manifestation but is not a
mediator variable which influences the
physiology/cause.
• Free will? Or physiology?
• Do you think you drive who you are, a
conscience that makes all the behavioural
decisions – free will. Is it something
different like physiology, a huge genetic
component that determines whether you
develop mental, developmental, or
behavioural disorders (we do not pick our
genes)?

• Disorders are not a decision, choice of free
will, it is genetic that they have no control
over! (Substance use, Alzheimer’s).

• Do not blame culture, don’t blame free will,
don’t believe the media representations of
neuroscience.

• Shock treatment etc. the best we can do?
The solutions we have are very limited,
small number of studies, ethical concerns
about potential risks of current treatment
options which we do not fully understand
the impact on physiology or the disorder
itself! Remember we are our physiology.

Question 31

Summary: Tourette’s

Answer 31

Summary: Tourette’s
• The cause of Tourette’s is unknown
• Tourette’s has a genetic component
• No gene[s] reliability confer risk of the
disorder
• Structural and functional findings implicate
the basal ganglia, limbic and frontal regions
in the pathophysiology of Tourette’s
• Dopamine is the most implicated system
• Other neurotransmitters are implicated in
TD due to their role in the cortico-ganglia
pathways and the effectiveness of non-
dopaminergic medications in treating TD
• Non-pharmacological interventions are
effective in reducing symptoms (i.e., CBT &
DBS)
• Preliminary evidence of adjunctive
interventions including botulinum toxin and
THC